A Phase I Trial of Pox PSA vaccines (PROSTVAC®-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM™) in Patients with Prostate Cancer

Purpose: Based on previous studies that demonstrated the safety profile and preliminary clinical activity of prostate specific antigen (PSA) targeted therapeutic vaccines, as well as recent laboratory data supporting the value of the addition of co-stimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM™) to these vaccines, we conducted a Phase I study to evaluate the safety and immunogenicity of a novel vaccinia and fowlpox vaccine incorporating the PSA gene sequence and TRICOM. Methods: In this study, ten patients with androgen independent prostate cancer with or without metastatic disease were enrolled. Patients were treated with 2 × l08 pfu of a recombinant vaccinia virus vaccine (PROSTVAC-V) followed by 1 × 109 pfu of the booster recombinant fowlpox virus (PROSTVAC-F) both with gene sequences for PSA and TRICOM. The mean age of patients enrolled in the study was 70 (range 63 to 79). The mean PSA at baseline was 434 (range 9 - 1424). Results: There were no deaths, and no Grade 3 or 4 adverse events. The most commonly reported adverse events, regardless of causality, were injection site reactions and fatigue. One serious adverse event (SAE) occurred that was unrelated to vaccine; this patient developed progressive disease with a new sphenoid metastasis. PSA was measured at week 4 and week 8. Four patients had stable disease (with less than 25% increase in PSA) through the week 8 study period. Anti-PSA antibodies were not induced with therapy: however, anti-vaccinia titers increased in all patients. Conclusion: This study demonstrated that vaccination with PROSTVAC-V and PROSTVAC-F combined with TRICOM is well-tolerated and generated an immune response to vaccinia. Therefore, PROSTVAC-VF/TRICOM represents a feasible therapeutic approach for further phase II and III study in patients with prostate cancer

Brokered Graph State Quantum Computing

We describe a procedure for graph state quantum computing that is tailored to fully exploit the physics of optically active multi-level systems. Leveraging ideas from the literature on distributed computation together with the recent work on probabilistic cluster state synthesis, our model assigns to each physical system two logical qubits: the broker and the client. Groups of brokers negotiate new graph state fragments via a probabilistic optical protocol. Completed fragments are mapped from broker to clients via a simple state transition and measurement. The clients, whose role is to store the nascent graph state long term, remain entirely insulated from failures during the brokerage. We describe an implementation in terms of NV-centres in diamond, where brokers and clients are very naturally embodied as electron and nuclear spins.Comment: 5 pages, 3 figure

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to dat

The ethics of uncertainty for data subjects

Modern health data practices come with many practical uncertainties. In this paper, I argue that data subjects’ trust in the institutions and organizations that control their data, and their ability to know their own moral obligations in relation to their data, are undermined by significant uncertainties regarding the what, how, and who of mass data collection and analysis. I conclude by considering how proposals for managing situations of high uncertainty might be applied to this problem. These emphasize increasing organizational flexibility, knowledge, and capacity, and reducing hazard

Air Pollution and the Dynamic Association Between Depressive Symptoms and Memory in Oldest-Old Women

BACKGROUND/OBJECTIVES Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women. DESIGN Prospective cohort data from the Women\u27s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. SETTING Geographically diverse community-dwelling population. PARTICIPANTS A total of 1,583 dementia-free women aged 80 and older. MEASUREMENTS Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5) (interquartile range [IQR] = 3.35 μg/m3) and gaseous nitrogen dioxide (NO2) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. RESULTS Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β = .287 per IQR; P = .002) and PM2.5 (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = −.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. CONCLUSION These findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women

Outdoor Air Pollution Exposure and Inter-relation of Global Cognitive Performance and Emotional Distress in Older Women

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM2.5 (particulate matter with aerodynamic diameter 2 (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women’s Health Initiative Memory Study. Annual exposure to PM2.5 (interquartile range [IQR] = 3.37 μg/m3) and NO2 (IQR = 9.00 ppb) was estimated at the participant’s residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM2.5 (β = -0.144 per IQR; 95% CI = −0.261; −0.028) and NO2 (β = −0.157 per IQR; 95% CI = −0.291; −0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (β = −0.008; 95% CI = −0.015; −0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM2.5 and NO2 exposure and emotional distress in later-life

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut.

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes

Mental Health and Substance Abuse Characteristics Among a Clinical Sample of Urban American Indian/Alaska Native Youths in a Large California Metropolitan Area: a Descriptive Study

This study analyzes descriptive data among a clinical sample of American Indian/Alaska Native (AI/AN) youths receiving mental health services in a large California metropolitan area. Among 118 urban AI/AN youths, mood disorders (41.5%) and adjustment disorder (35.4%) were the most common mental health diagnoses. Alcohol (69.2%) and marijuana (50.0%) were the most commonly used substances. Witnessing domestic violence (84.2%) and living with someone who had a substance abuse problem (64.7%) were reported. The majority of patients demonstrated various behavior and emotional problems. Enhancing culturally relevant mental health and substance abuse treatment and prevention programs for urban AI/AN youth is suggested